Abstract：
The phase angle (PhA) measured with bioelectrical impedance analysis is considered to reflect the interrelated components body cell mass and fluid distribution based on technical and physical aspects of the PhA measurement. However, the biomedical meaning of the PhA remains vague. Previous studies mainly assessed associations of the PhA with numerous diseases and health outcomes, but few connected protein markers to the PhA. To broaden our understanding of the biomedical background of the PhA, we aimed to explore a proteomics profile associated with the PhA and related biological factors.
The study sample encompassed 1484 participants (725 women and 759 men) aged 55-74 years from the population-based Cooperative Health Research in the Region of Augsburg (KORA) S4 study. Proteomics measurements were performed with a proximity extension assay. We employed boosting with stability selection to establish a set of markers that was strongly associated with the PhA from a group of 233 plasma protein markers. We integrated the selected protein markers into a network and enrichment analysis to identify gene ontology (GO) terms significantly overrepresented for the selected PhA protein markers.
Boosting with stability selection identified seven protein markers that were strongly and independently associated with the PhA: N-terminal prohormone brain natriuretic peptide (NT-proBNP), insulin-like growth factor-binding protein 2 (IGFBP2), adrenomedullin (ADM), myoglobin (MB), matrix metalloproteinase-9 (MMP9), protein-glutamine gamma-glutamyltransferase 2 (TGM2), and fractalkine (CX3CL1) [beta coefficient per 1 standard deviation increase in normalized protein expression values on a log 2 scale (95% confidence interval): -0.12 (-0.15, -0.08), -0.13 (-0.17, -0.09), -0.14 (-0.18, -0.10), 0.10 (0.07, 0.14), 0.07 (0.04, 0.10), 0.08 (0.05, 0.11), -0.06 (-0.10, -0.03), respectively]. According to the enrichment analysis, this protein profile was significantly overrepresented in the following top five GO terms: positive regulation of cell population proliferation (p-value: 1.32E-04), extracellular space (p-value: 1.34E-04), anatomical structure formation involved in morphogenesis (p-value: 2.92E-04), regulation of multicellular organismal development (p-value: 5.72E-04), and metal ion homeostasis (p-value: 8.86E-04).
Implementing a proteomics approach, we identified six new protein markers strongly associated with the PhA and confirmed that NT-proBNP is a key PhA marker. The main biological processes that were related to this PhA\'s protein profile are involved in regulating the amount and growth of cells, reinforcing, from a biomedical perspective, the current technical-based consensus of the PhA to reflect body cell mass.
The study sample encompassed 1484 participants (725 women and 759 men) aged 55-74 years from the population-based Cooperative Health Research in the Region of Augsburg (KORA) S4 study. Proteomics measurements were performed with a proximity extension assay. We employed boosting with stability selection to establish a set of markers that was strongly associated with the PhA from a group of 233 plasma protein markers. We integrated the selected protein markers into a network and enrichment analysis to identify gene ontology (GO) terms significantly overrepresented for the selected PhA protein markers.
Boosting with stability selection identified seven protein markers that were strongly and independently associated with the PhA: N-terminal prohormone brain natriuretic peptide (NT-proBNP), insulin-like growth factor-binding protein 2 (IGFBP2), adrenomedullin (ADM), myoglobin (MB), matrix metalloproteinase-9 (MMP9), protein-glutamine gamma-glutamyltransferase 2 (TGM2), and fractalkine (CX3CL1) [beta coefficient per 1 standard deviation increase in normalized protein expression values on a log 2 scale (95% confidence interval): -0.12 (-0.15, -0.08), -0.13 (-0.17, -0.09), -0.14 (-0.18, -0.10), 0.10 (0.07, 0.14), 0.07 (0.04, 0.10), 0.08 (0.05, 0.11), -0.06 (-0.10, -0.03), respectively]. According to the enrichment analysis, this protein profile was significantly overrepresented in the following top five GO terms: positive regulation of cell population proliferation (p-value: 1.32E-04), extracellular space (p-value: 1.34E-04), anatomical structure formation involved in morphogenesis (p-value: 2.92E-04), regulation of multicellular organismal development (p-value: 5.72E-04), and metal ion homeostasis (p-value: 8.86E-04).
Implementing a proteomics approach, we identified six new protein markers strongly associated with the PhA and confirmed that NT-proBNP is a key PhA marker. The main biological processes that were related to this PhA\'s protein profile are involved in regulating the amount and growth of cells, reinforcing, from a biomedical perspective, the current technical-based consensus of the PhA to reflect body cell mass.
摘要：
根据PhA测量的技术和物理方面，使用生物电阻抗分析测量的相位角（PhA）被认为反映了相互关联的身体细胞质量和流体分布。然而,PhA的生物医学含义仍然模糊。以前的研究主要评估了PhA与许多疾病和健康结果的关联，但是很少有与PhA相关的蛋白质标记。为了扩大我们对PhA生物医学背景的理解，我们旨在探索与PhA和相关生物学因素相关的蛋白质组学概况。
研究样本包括1484名参与者（725名女性和759名男性），年龄在55-74岁之间，来自奥格斯堡地区（KORA）S4研究的基于人群的合作健康研究。用邻近延伸测定进行蛋白质组学测量。我们采用增强稳定性选择来建立一组与来自一组233个血浆蛋白标志物的PhA强烈相关的标志物。我们将所选的蛋白质标记物整合到网络和富集分析中，以识别所选PhA蛋白质标记物明显过度代表的基因本体论（GO）术语。
通过稳定性选择进行增强，鉴定出与PhA：N末端激素原脑钠肽（NT-proBNP）强烈且独立相关的七个蛋白质标记，胰岛素样生长因子结合蛋白2（IGFBP2），肾上腺髓质素(ADM),肌红蛋白(MB),基质金属蛋白酶-9（MMP9），蛋白-谷氨酰胺γ-谷氨酰转移酶2（TGM2），和fractalkine（CX3CL1）[在log2量表（95％置信区间）上，标准化蛋白质表达值每1个标准偏差增加的β系数：-0.12（-0.15，-0.08），-0.13（-0.17，-0.09），-0.14（-0.18，-0.10），0.10(0.07,0.14),0.07(0.04,0.10),0.08（0.05，0.11），-0.06(-0.10,-0.03),分别]。根据富集分析，该蛋白质谱在以下前五个GO术语中被显著地过度表示:细胞群体增殖的正调节(p值:1.32E-04),细胞外空间（p值：1.34E-04），与形态发生有关的解剖结构形成（p值：2.92E-04），多细胞组织发育的调节（p值：5.72E-04），和金属离子稳态(p值：8.86E-04)。
实施蛋白质组学方法，我们鉴定出6个与PhA密切相关的新蛋白标志物,并证实NT-proBNP是一个关键的PhA标志物.与此PhA蛋白谱相关的主要生物学过程涉及调节细胞的数量和生长，加强，从生物医学的角度来看，目前基于技术的PhA反映身体细胞质量的共识。
研究样本包括1484名参与者（725名女性和759名男性），年龄在55-74岁之间，来自奥格斯堡地区（KORA）S4研究的基于人群的合作健康研究。用邻近延伸测定进行蛋白质组学测量。我们采用增强稳定性选择来建立一组与来自一组233个血浆蛋白标志物的PhA强烈相关的标志物。我们将所选的蛋白质标记物整合到网络和富集分析中，以识别所选PhA蛋白质标记物明显过度代表的基因本体论（GO）术语。
通过稳定性选择进行增强，鉴定出与PhA：N末端激素原脑钠肽（NT-proBNP）强烈且独立相关的七个蛋白质标记，胰岛素样生长因子结合蛋白2（IGFBP2），肾上腺髓质素(ADM),肌红蛋白(MB),基质金属蛋白酶-9（MMP9），蛋白-谷氨酰胺γ-谷氨酰转移酶2（TGM2），和fractalkine（CX3CL1）[在log2量表（95％置信区间）上，标准化蛋白质表达值每1个标准偏差增加的β系数：-0.12（-0.15，-0.08），-0.13（-0.17，-0.09），-0.14（-0.18，-0.10），0.10(0.07,0.14),0.07(0.04,0.10),0.08（0.05，0.11），-0.06(-0.10,-0.03),分别]。根据富集分析，该蛋白质谱在以下前五个GO术语中被显著地过度表示:细胞群体增殖的正调节(p值:1.32E-04),细胞外空间（p值：1.34E-04），与形态发生有关的解剖结构形成（p值：2.92E-04），多细胞组织发育的调节（p值：5.72E-04），和金属离子稳态(p值：8.86E-04)。
实施蛋白质组学方法，我们鉴定出6个与PhA密切相关的新蛋白标志物,并证实NT-proBNP是一个关键的PhA标志物.与此PhA蛋白谱相关的主要生物学过程涉及调节细胞的数量和生长，加强，从生物医学的角度来看，目前基于技术的PhA反映身体细胞质量的共识。
